The clinical utility of topical drug administration is critically dependent on improved delivery systems that will allow the administration of therapeutics that are difficult for the body to take up. Within this context, amphiphilic, biodegradable polymers that can self assemble into nano-sized structures have been identified as a promising platform for the development of cutaneous delivery carriers. There is also consensus that a better understanding of the complex interactions that control the biological responses of cells and tissue to nano- sized carriers is of high importance. This application addresses both issues. Our unique nanosphere system is based on a biodegradable, biocompatible, and non-cytotoxic polymer that provides a high degree of structural versatility for complexing lipophilic therapeutics. The nanospheres were formed by the self-assembly of ABA- type amphiphilic triblock copolymer derived exclusively from natural metabolites. A-blocks are poly(ethylene glycol), PEG, and hydrophobic B-blocks are oligomers of desaminotyrosyl-tyrosine alkyl esters (DTR) and non- toxic diacids. The choice of oligo(DTR-diacid) for the middle block was based on its tunable hydrophobicity and degradability under physiological conditions. Modulation of cell behavior and non-fouling characteristics of non- cytotoxic and biocompatible PEG makes it attractive for in vivo applications. Additionally, the presence of PEG could provide superior hydration of the skin thereby increasing the skin permeation ability of nanospheres. No other group has demonstrated successful topical skin delivery in vitro using hollow nanospheres based on a fully biodegradable, self-assembling triblock copolymer that possesses immunomodulatory activities of tissue necrosis factor antagonists. Our nanospheres significantly enhanced skin penetration of highly lipophilic model agents in human cadaver skin compared to a non-particulate formulation. No detectable transdermal permeation was observed even after 24 hours application, suggesting that these nanospheres can be used in topical drug delivery. In addition, major advantages of the polymeric system proposed here include (i) ease of formulation of nano-sized hollow spheres in an ideal size range and narrow distribution, (ii) complete degradability, (iii) non-toxicity, and (iv) chemical diversity allowing for structural modifications and optimization. We plan to use this novel approach to identify a set of generally applicable design parameters for the development of optimized and biologically compatible topical delivery carriers. Our goal is to study the feasibility of tyrosine-derived nanospheres as delivery vehicles for a wide range of lipophilic drugs into the skin as well as nanospheres interactions with healthy and diseased skin. This would result in better understanding of the barriers to efficient topical delivery and promote the design of a formulation for the delivery of psoriasis therapeutics. If successful, the concepts proposed here have the potential to contribute significantly to the future development of skin-targeted applications. Biodegradable non-cytotoxic nanospheres loaded with lipophilic therapeutics will be prepared and optimized for the efficient delivery of drugs into the skin. These topical agents will provide new therapeutic avenues for the treatment of psoriasis while minimizing systemic cytotoxicity of harsh therapeutics. The nanosphere design is highly versatile and will significantly contribute to topical drug delivery applications. [unreadable] [unreadable] [unreadable]